Piperacillin and Tazobactam

1 INDICATIONS AND USAGE Piperacillin and tazobactam for injection, for intravenous use is a combination of piperacillin, a penicillin-class antibacterial and tazobactam, a beta-lactamase inhibitor, indicated for the treatment of: Intra-abdominal infections in adult and pediatric patients 2 months of age and older ( 1.1 ) Nosocomial pneumonia in adult and pediatric patients 2 months of age and older ( 1.2 ) Skin and skin structure infections in adults ( 1.3 ) Female pelvic infections in adults ( 1.4 ) Community-acquired pneumonia in adults ( 1.5 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Piperacillin and tazobactam and other antibacterial drugs, piperacillin and tazobactam for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.6 ) 1.1 Intra-abdominal Infections Piperacillin and tazobactam is indicated in adults and pediatric patients (2 months of age and older) for the treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by beta-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron , or B. vulgatus . 1.2 Nosocomial Pneumonia Piperacillin and tazobactam is indicated in adults and pediatric patients (2 months of age and older) for the treatment of nosocomial pneumonia (moderate to severe) caused by beta-lactamase producing isolates of Staphylococcus aureus and by piperacillin and tazobactam-susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae , and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P. aeruginosa should be treated in combination with an aminoglycoside) [see Dosage and Administration (2) ] . 1.3 Skin and Skin Structure Infections Piperacillin and tazobactam is indicated in adults for the treatment of uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by beta-lactamase producing isolates of Staphylococcus aureus . 1.4 Female Pelvic Infections Piperacillin and tazobactam is indicated in adults for the treatment of postpartum endometritis or pelvic inflammatory disease caused by beta-lactamase producing isolates of Escherichia coli . 1.5 Community-acquired Pneumonia Piperacillin and tazobactam is indicated in adults for the treatment of community-acquired pneumonia (moderate severity only) caused by beta-lactamase producing isolates of Haemophilus influenzae . 1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Piperacillin and tazobactam and other antibacterial drugs, Piperacillin and tazobactam should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION Adult Patients With Indications Other Than Nosocomial Pneumonia: The usual daily dosage of Piperacillin and tazobactam for injection for adults is 3.375 g every six hours totaling 13.5 g (12 g piperacillin and 1.5 g tazobactam). ( 2.1 ) Adult Patients with Nosocomial Pneumonia : Initial presumptive treatment of patients with nosocomial pneumonia should start with Piperacillin and tazobactam for injection at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18 g (16 g piperacillin and 2 g tazobactam). ( 2.2 ) Adult Patients with Renal Impairment : Dosage in patients with renal impairment (creatinine clearance ≤40 mL/min) and dialysis patients should be reduced, based on the degree of renal impairment. ( 2.3 ) Pediatric Patients by Indication and Age : See Table below ( 2.4 ) Recommended Dosage of Piperacillin and tazobactam for Pediatric Patients 2 months of Age and Older, Weighing up to 40 Kg and With Normal Renal Function Age Appendicitis and/or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 ( eight ) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 ( six ) hours Older than 9 months 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 ( eight ) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 6 ( six ) hours Administer Piperacillin and tazobactam by intravenous infusion over 30 minutes to both adult and pediatric patients. ( 2.1 , 2.2 , 2.3 , 2.4 ) Piperacillin and tazobactam and aminoglycosides should be reconstituted, diluted, and administered separately. Co-administration via Y-site can be done under certain conditions. ( 2.6 ) See the full prescribing information for the preparation and administration instructions for Piperacillin and tazobactam for injection single-dose vials. 2.1 Dosage in Adult Patients With Indications Other Than Nosocomial Pneumonia The usual total daily dosage of Piperacillin and tazobactam for adult patients with indications other than nosocomial pneumonia is 3.375 g every six hours [totaling 13.5 g (12 g piperacillin and 1.5 g tazobactam)], to be administered by intravenous infusion over 30 minutes. The usual duration of Piperacillin and tazobactam treatment is from 7 to 10 days. 2.2 Dosage in Adult Patients With Nosocomial Pneumonia Initial presumptive treatment of adult patients with nosocomial pneumonia should start with Piperacillin and tazobactam at a dosage of 4.5 g every six hours plus an aminoglycoside, [totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam)], administered by intravenous infusion over 30 minutes. The recommended duration of Piperacillin and tazobactam treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated. 2.3 Dosage in Adult Patients With Renal Impairment In adult patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of Piperacillin and tazobactam should be reduced based on the degree of renal impairment. The recommended daily dosage of Piperacillin and tazobactam for patients with renal impairment administered by intravenous infusion over 30 minutes is described in Table 1. Table 1: Recommended Dosage of Piperacillin and tazobactam in Patients with Normal Renal Function and Renal Impairment (as total grams piperacillin and tazobactam) a Creatinine clearance, mL/min All Indications (except nosocomial pneumonia) Nosocomial Pneumonia a Administer piperacillin and tazobactam for injection by intravenous infusion over 30 minutes. b Creatinine clearance for patients not receiving hemodialysis c 0.75 g (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days Greater than 40 mL/min 3.375 every 6 hours 4.5 every 6 hours 20 to 40 mL/min b 2.25 every 6 hours 3.375 every 6 hours Le…

5 WARNINGS AND PRECAUTIONS Serious hypersensitivity reactions (anaphylactic/anaphylactoid) reactions have been reported in patients receiving piperacillin and tazobactam. Discontinue piperacillin and tazobactam if a reaction occurs. ( 5.1 ) Piperacillin and tazobactam may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. Discontinue Piperacillin and tazobactam for progressive rashes. ( 5.2 ) Hemophagocytic lymphohistiocytosis (HLH) has been reported with the use of Piperacillin and tazobactam. If HLH is suspected, discontinue Piperacillin and tazobactam immediately. ( 5.3 ) Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue Piperacillin and tazobactam for injection and initiate appropriate therapy. ( 5.4 ) Hematological effects (including bleeding, leukopenia and neutropenia) have occurred. Monitor hematologic tests during prolonged therapy. ( 5.5 ) As with other penicillins, Piperacillin and tazobactam may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially in the presence of renal impairment may be at greater risk. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures. ( 5.6 ) Nephrotoxicity in critically ill patients has been observed; the use of Piperacillin and tazobactam was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with Piperacillin and tazobactam. ( 5.7 ) Clostridioides difficile -associated diarrhea: evaluate patients if diarrhea occurs. ( 5.9 ) 5.1 Hypersensitivity Adverse Reactions Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with Piperacillin and tazobactam. These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with piperacillin and tazobactam for injection, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, Piperacillin and tazobactam should be discontinued and appropriate therapy instituted. 5.2 Severe Cutaneous Adverse Reactions ​Piperacillin and tazobactam may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and Piperacillin and tazobactam discontinued if lesions progress. 5.3 Hemophagocytic Lymphohistiocytosis Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in pediatric and adult patients treated with Piperacillin and tazobactam. Signs and symptoms of HLH may include fever, rash, lymphadenopathy, hepatosplenomegaly and cytopenia. If HLH is suspected, discontinue Piperacillin and tazobactam immediately and institute appropriate management. 5.4 Rhabdomyolysis Rhabdomyolysis has been reported with the use of Piperacillin and tazobactam [see Adverse Reactions (6.2) ]. If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue Piperacillin and tazobactam for injection and initiate appropriate therapy. 5.5 Hematologic Adverse Reactions Bleeding manifestations h…

4 CONTRAINDICATIONS Piperacillin and tazobactam is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. Patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. ( 4 )

7 DRUG INTERACTIONS Piperacillin and tazobactam administration can significantly reduce tobramycin concentrations in hemodialysis patients. Monitor tobramycin concentrations in these patients. ( 7.1 ) Probenecid prolongs the half-lives of Piperacillin and tazobactam and should not be co-administered with Piperacillin and tazobactam unless the benefit outweighs the risk. ( 7.2 ) Co-administration of Piperacillin and tazobactam with vancomycin may increase the incidence of acute kidney injury. Monitor kidney function in patients receiving Piperacillin and tazobactam and vancomycin. ( 7.3 ) Monitor coagulation parameters in patients receiving Piperacillin and tazobactam and heparin or oral anticoagulants. ( 7.4 ) Piperacillin and tazobactam may prolong the neuromuscular blockade of vecuronium and other non-depolarizing neuromuscular blockers. Monitor for adverse reactions related to neuromuscular blockade. ( 7.5 ) 7.1 Aminoglycosides Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides. In vivo inactivation: When aminoglycosides are administered in conjunction with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored. Sequential administration of Piperacillin and tazobactam for injection and tobramycin to patients with either normal renal function or mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but no dosage adjustment is considered necessary. In vitro inactivation: Due to the in vitro inactivation of aminoglycosides by piperacillin, Piperacillin and tazobactam and aminoglycosides are recommended for separate administration. Piperacillin and tazobactam and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. Piperacillin and tazobactam is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations. Piperacillin and tazobactam is not compatible with tobramycin for simultaneous Y-site infusion [see Dosage and Administration (2.6) ]. 7.2 Probenecid Probenecid administered concomitantly with Piperacillin and tazobactam prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both Piperacillin and tazobactam. Probenecid should not be co-administered with piperacillin and tazobactam unless the benefit outweighs the risk. 7.3 Vancomycin Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin and tazobactam and vancomycin as compared to vancomycin alone [see Warnings and Precautions (5.6) ]. Monitor kidney function in patients concomitantly administered with piperacillin and tazobactam and vancomycin. No pharmacokinetic interactions have been noted between piperacillin and tazobactam and vancomycin. 7.4 Anticoagulants Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function [see Warnings and Precautions (5.4) ]. 7.5 Vecuronium Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Piperacillin and tazobactam could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing neuromuscular blockers could be prolonged in the presence of piperacillin. Monitor for adverse reactions related to neuromuscular blockade (see package insert for vecuronium bromide). 7.6 Methotrexate Limited data suggests that co-administration o…

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Adverse Reactions [see Warnings and Precautions (5.1) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2) ] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.3) ] Rhabdomyolysis [see Warnings and Precautions (5.4) ] Hematologic Adverse Reactions [see Warnings and Precautions (5.5) ] Central Nervous System Adverse Reactions [see Warnings and Precautions (5.6) ] Nephrotoxicity in Critically Ill Patients [see Warnings and Precautions (5.7) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.9) ] The most common adverse reactions (incidence >5%) are diarrhea, constipation, nausea, headache, and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Civica, Inc. at 1-833-224-2004 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Patients During the initial clinical investigations, 2621 patients worldwide were treated with Piperacillin and tazobactam in phase 3 trials. In the key North American monotherapy clinical trials (n=830 patients), 90% of the adverse events reported were mild to moderate in severity and transient in nature. However, in 3.2% of the patients treated worldwide, Piperacillin and tazobactam was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritus; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%). Table 5: Adverse Reactions from Piperacillin and Tazobactam Monotherapy Clinical Trials System Organ Class Adverse Reaction Gastrointestinal disorders Diarrhea (11.3%) Constipation (7.7%) Nausea (6.9%) Vomiting (3.3%) Dyspepsia (3.3%) Abdominal pain (1.3%) General disorders and administration site conditions Fever (2.4%) Injection site reaction (≤1%) Rigors (≤1%) Immune system disorders Anaphylaxis (≤1%) Infections and infestations Candidiasis (1.6%) Pseudomembranous colitis (≤1%) Metabolism and nutrition disorders Hypoglycemia (≤1%) Musculoskeletal and connective tissue disorders Myalgia (≤1%) Arthralgia (≤1%) Nervous system disorders Headache (7.7%) Psychiatric disorders Insomnia (6.6%) Skin and subcutaneous tissue disorders Rash (4.2%, including maculopapular, bullous, and urticarial) Pruritus (3.1%) Purpura (≤1%) Vascular disorders Phlebitis (1.3%) Thrombophlebitis (≤1%) Hypotension (≤1%) Flushing (≤1%) Respiratory, thoracic and mediastinal disorders Epistaxis (≤1%) Nosocomial Pneumonia Trials Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with Piperacillin and tazobactam in a dosing regimen of 4.5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg every 6 hours) in combination with an aminoglycoside. In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin and tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11%) patients in the piperacillin and tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p > 0.05) discontinued treatment due to an adverse event. The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside. Table 6: Adverse Reactions from Piperacillin and Tazobactam Plus Aminoglycoside Clinical Trials a a For adverse drug reactions that appeared in both studies the higher frequency is presented. System Organ Class Adverse Reaction Blood and lymphatic system disorders Thrombocythemia (1.4%) Anemia (≤1%) Thrombocy…